Deuterated drugs are widely used in studies of metabolism of drugs and toxic substances in humans and other animals. The deuterated forms of drugs often have different actions than the protonated forms. Some deuterated drugs show different transport processes. Most are more resistant to metabolic changes, especially those changes mediated by cytochrome P450 systems. Deuteration may also change the pathway of drug metabolism (metabolic switching). Changed metabolism may lead to increased duration of action and lower toxicity. It may also lead to lower activity, if the drug is normally changed to the active form in vivo. Deuteration can also lower the genotoxicity of the anticancer drug tamoxifen and other compounds. Deuteration increases effectiveness of long-chain fatty acids and fluoro-D-phenylalanine by preventing their breakdown by target microorganisms.
Deuterium (D) is a nonradioactive isotope which contains one additional neutron than the normally abundant isotope of hydrogen which does not contain any neutrons. Deuterium behaves similarly to ordinary hydrogen, but it can be distinguished from ordinary hydrogen by its mass using mass spectrometry or infrared spectrometry. Consequently, deuterated compounds have been long used in pharmaceutical research to investigate the in vivo metabolic fate of the compounds by evaluation of the mechanism of action and metabolic-pathway of the non deuterated parent compound. Such metabolic studies are important in the design of safe, effective therapeutic drugs.
Incorporation of deuterium for a hydrogen atom in a drug can give rise to an isotope effect that can alter the pharmacokinetics of the drug. This effect is usually insignificant if the label is placed in a molecule at the metabolically inert position of the molecule. For instance, deuteration, as exemplified by deuterated Rapamycin (see U.S. Pat. No. 6,503,921), Cyclosporine (see U.S. Pat. No. 6,613,739) or Nifedipine (see U.S. Pat. No. 5,846,514) has been reported to alter the pharmacokinetics of a drug. Forster et al. (Isotechnica, AB) have shown that deuteration can enhance duration of action.
Deuterium-labeling of a drug can alter its physico-chemical properties such as pKa and lipid solubility. These changes may influence the fate of the drug at different steps along its passage through the body. Absorption, distribution, metabolism or excretion can be changed. Absorption and distribution are processes that depend primarily on the molecular size and the lipophilicity of the substance.
Drug metabolism can give rise to large isotopic effect if the breaking of a chemical bond to a deuterium atom is the rate limiting step in the process. While some of the physical properties of a deuterium-labeled molecule are different from those of the unlabeled one, the chemical and biological properties are the same, with one important exception: because of the increased mass of the heavy isotope, any bond involving the heavy isotope and another atom will be stronger than the same bond between the light isotope and that atom. In any reaction in which the breaking of this bond is the rate limiting step, the reaction will proceed slower for the molecule with the heavy isotope due to kinetic isotope effect. A reaction involving breaking a C-D bond can be up to 700 percent slower than a similar reaction involving breaking a C—H bond.
More caution has to be observed when using deuterium-labeled drugs. If the C-D bored is not involved in any of the steps leading to the metabolite, there may not be any effect to alter the behavior of the drug. If deuterium is placed at a site involved in the metabolism of a drug, an isotope effect will be observed only if breaking of the C-D bond is the rate limiting step. There are evidences to suggest that whenever cleavage of an aliphatic C—H bond occurs, usually by oxidation catalyzed by a mixed-function oxidase, replacement of the hydrogen by deuterium will lead to observable isotope effect. It is also important to understand that the incorporation of deuterium at the site of metabolism slows its rate to the point where another metabolite produced by attack at a carbon atom not substituted by deuterium becomes the major pathway by a process called “metabolic switching”.
It is also observed that one of the most important metabolic pathways of compounds containing aromatic systems is hydroxylation leading to a phenolic group in the 3 or 4 position to carbon substituents. Although this pathway involves cleavage of the C—H bond, it is often not accompanied by an isotope effect, because the cleavage of this bond is mostly not involved in the rate-limiting step. The substitution of hydrogen by deuterium at the stereo center will induce a greater effect on the activity of the drug.
Clinically relevant questions with respect to deuterium-labeled drugs include the toxicity of the drug and its metabolite derivatives, the changes in distribution or elimination (enzyme induction), lipophilicity which will have an effect on absorption of the drug. Replacement of hydrogen by deuterium at the site involving the metabolic reaction will lead to increased toxicity of the drug. Replacement of hydrogen by deuterium at the aliphatic carbons will have an isotopic effect to a larger extent. Deuterium placed at an aromatic carbon atom, which will be the site of hydroxylation, may lead to an observable isotope effect, although this is less often the case than with aliphatic carbons. In few cases, such as in penicillin, the substitution on the aromatic ring will induce the restriction of rotation of the ring around the C—C bond leading to a favorable stereo-specific situation to enhance the activity of the drug.
Side-effects with acute deuterium dosing have been shown to be transitory with no demonstrated evidence of permanent deleterious action. The threshold of deuterium toxicity has been defined in animals and is far in excess of concentrations conceivably used in human studies. The possibility that deuterium may have additional beneficial pharmacological applications can therefore not be excluded.
PCT Published Patent Application, WO 2004/099137 discloses a class of aminocyclohexyl ether compounds as being useful in the treatment of arrhythmias. One class of compounds disclosed therein are particularly effective in the treatment and/or prevention of arrhythmia, particularly atrial fibrillation.
There exists, therefore, a need to prepare deuterated compounds which can be used, inter alia, as standards or tracer molecules in biological or bioanalytical assays in order to determine the biological effectiveness and metabolic pathway for a class of compounds disclosed in PCT Published Patent Application WO 99/50225.